Venofer® (iron sucrose injection, USP) is a brown, sterile, aqueous, complex of polynuclear iron (III)- hydroxide in sucrose for intravenous use. Iron sucrose injection has a molecular weight of approximately 34,000 - 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH)·3(H₂O)]_n · m(C₁₂H₂₂O₁₁)

where: n is the degree of iron polymerization and m is the number of sucrose molecules associated with the iron (III)-hydroxide.

Each mL contains 20 mg elemental iron as iron sucrose in water for injection. Venofer® is available in 5 mL single dose vials (100 mg elemental iron per 5 mL) and 10 mL single dose vials (200 mg elemental iron per 10 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5- 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

Therapeutic class: Hematinic

Last updated on RxList: 1/2/2008

Venofer® is indicated in the treatment of iron deficiency anemia in the following patients:

• non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin
• non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin
• hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving an erythropoietin
• peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving an erythropoietin.

The dosage of Venofer® is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron.

Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin response and to replenish iron stores (ferritin, TSAT). Hemodialysis patients may continue to require therapy with Venofer® or other intravenous iron preparations at the lowest dose necessary to maintain target levels of hemoglobin, and laboratory parameters of iron storage within acceptable limits.

Administration: Venofer® must only be administered intravenously either by slow injection or by infusion.

Recommended Adult Dosage

Hemodialysis Dependent-Chronic Kidney Disease Patients (HDD-CKD): Venofer® may be administered undiluted as a 100 mg slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes per consecutive hemodialysis session for a total cumulative dose of 1,000 mg.

Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer®, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See Clinical Trials, Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD- CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients sections.)

Peritoneal Dialysis Dependent-Chronic Kidney Disease Patients (PDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. The Venofer® dose should be diluted in a maximum of 250 mL of 0.9% NaCl.

Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL). Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F). [See the USP controlled room temperature]. Do not freeze.

Sterile

NDC-0517-2340-01   100 mg/5 mL Single Dose Vial   Individually Boxed
NDC-0517-2340-10   100 mg/5 mL Single Dose Vial   Packages of 10
NDC-0517-2340-25   100 mg/5 mL Single Dose Vial   Packages of 25
NDC-0517-2310-01   200 mg/10 mL Single Dose Vial   Individually Boxed
NDC-0517-2310-10   200 mg/10 mL Single Dose Vial   Packages of 10

AMERICAN REGENT, INC. SHIRLEY, NY 11967. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. FDA Rev date: 12/3/2007

Last updated on RxList: 1/2/2008

Adverse Events observed in all treated populations

The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition, over 2,000 patients treated with Venofer® have been reported in the medical literature.

Treatment-emergent adverse events reported by ≥ 2% of treated patients in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2.

Table 2. Most Common Treatment-Emergent Adverse Events Reported in ≥ 2% of Patients By Clinical Indication (Multidose Safety Population)

Adverse Events (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Venofer® (N=231) %	Venofer® (N=139) %	Oral Iron (N=139) %	Venofer® (N=75) %	EPO Only (N=46) %
Subjects with any adverse event	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain NOS*	3.5	1.4	2.9	4.0	6.5
Constipation	1.3	4.3	12.9	4.0	6.5
Diarrhea NOS	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting NOS	9.1	5.0	8.6	8.0	2.2
General Disorders and Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Edema NOS	0.4	6.5	6.5	0	2.2
Fatigue	1.7	3.6	5.8	0	4.3
Feeling abnormal	3.0	0	0	0	0
Infusion site burning	0	3.6	0	0	0
Injection site extravasation	0	2.2	0	0	0
Injection site pain	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Catheter site infection	0	0	0	4.0	8.7
Nasopharyngitis	0.9	0.7	2.2	2.7	2.2
Peritoneal infection	0	0	0	8.0	10.9
Sinusitis NOS	0	0.7	0.7	4.0	0
Upper respiratory tract infection NOS	1.3	0.7	1.4	2.7	2.2
Urinary tract infection NOS	0.4	0.7	5.0	1.3	2.2
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Investigations
Cardiac murmur NOS	0.4	2.2	2.2	0	0
Fecal occult blood positive	0	1.4	3.6	2.7	4.3
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia NOS	0	2.9	0	0	2.2
Hypoglycemia NOS	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Arthritis NOS	0	0	0	0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Hypoesthesia	0	0.7	0.7	0	4.3
Respiratory, Thoracic and Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	3.6	0.7	1.3	2.2
Dyspnea exacerbated	0	2.2	0.7	0	0
Nasal congestion	0	1.4	2.2	1.3	0
Pharyngitis	0.4	0	0	6.7	0
Rhinitis allergic NOS	0	0.7	2.2	0	0
Skin and Subcutaneous Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Rash NOS	0.4	1.4	2.2	0	2.2
Vascular Disorders
Hypertension NOS	6.5	6.5	4.3	8.0	6.5
Hypotension NOS	39.4	2.2	0.7	2.7	2.2
*NOS=Not otherwise specified

Treatment-emergent adverse events reported in ≥ 2% of patients by dose group are shown in Table 3.

Table 3. Most Common Treatment-Emergent Adverse Events Reported in ≥ 2% of Patients by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term)	HDD-CKD 100 mg (N=231) %	NDD-CKD		PDD-CKD
		200 mg (N=109) %	500 mg (N=30) %	300 mg for 2 doses followed by 400 mg for 1 dose (N= 75)
Subjects with any adverse event	78.8	75.2	80.0	%72.0
Ear and Labyrinth Disorders
Ear pain	0	0.9	6.7	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7
Gastrointestinal Disorders
Abdominal pain NOS*	3.5	1.8	0	4.0
Constipation	1.3	3.7	6.7	4.0
Diarrhea NOS	5.2	6.4	10.0	8.0
Dysgeusia	0.9	9.2	3.3	0
Nausea	14.7	9.2	6.7	5.3
Vomiting NOS	9.1	5.5	3.3	8.0
General Disorders and Administration Site Conditions
Asthenia	2.2	0.9	0	2.7
Chest pain	6.1	0.9	3.3	2.7
Edema NOS	0.4	7.3	3.3	0
Fatigue	1.7	4.6	0	0
Feeling abnormal	3.0	0	0	0
Infusion site burning	0	3.7	3.3	0
Injection site pain	0	2.8	0	0
Peripheral edema	2.6	5.5	13.3	5.3
Pyrexia	3.0	0.9	0	1.3
Infections and Infestations
Catheter site infection	0	0	0	4.0
Nasopharyngitis	0.9	0.9	0	2.7
Peritoneal infection	0	0	0	8.0
Sinusitis NOS	0	0	3.3	4
Upper respiratory tract infection	1.3	0.9	0	2.7
Injury, Poisoning and Procedural Complications
Graft complication	9.5	1.8	0	0
Investigations
Cardiac murmur NOS	0.4	2.8	0	0
Fecal occult blood positive	0	1.8	0	2.7
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.8	0	1.3
Gout	0	1.8	6.7	0
Hyperglycemia NOS	0	3.7	0	0
Hypoglycemia NOS	0.4	0.9	0	4.0
Musculoskeletal and Connective Tissue Disorders
Arthralgia	3.5	0.9	3.3	4.0
Back pain	2.2	1.8	3.3	1.3
Muscle cramp	29.4	0	3.3	2.7
Myalgia	0	2.8	6.7	1.3
Pain in extremity	5.6	4.6	3.3	2.7
Nervous System Disorders
Dizziness	6.5	5.5	10.0	1.3
Headache	12.6	3.7	0	4.0
Respiratory, Thoracic and Mediastinal Disorders
Cough	3.0	0.9	6.7	1.3
Dyspnea	3.5	1.8	10.0	1.3
Pharyngitis	0.4	0	0	6.7
Skin and Subcutaneous Tissue Disorders
Pruritus	3.9	0.9	6.7	2.7
Vascular Disorders
Hypertension NOS	6.5	6.4	6.7	8.0
Hypotension NOS	39.4	0.9	6.7	2.7
*NOS=Not otherwise specified

Drug related adverse events reported by ≥ 2% of Venofer® treated patients are shown by dose group in Table 4.

Table 4. Most Common Adverse Events Related to Study Drug Reported in ≥ 2% of Patients by Dose Group (Multidose Safety Population)

	HDD-CKD	NDD-CKD		PDD-CKD
Adverse Events (Preferred Term)	100 mg (N=231) %	200 mg (N=109) %	500 mg (N=30) %	300 mg for 2 doses followed by 400 mgfor 1 dose (N= 75)
Subjects with any adverse event	14.7	23.9	20.0	%10.7
Gastrointestinal Disorders
Diarrhea NOS*	0.9	0	0	2.7
Dysgeusia	0.9	7.3	3.3	0
Nausea	1.7	2.8	0	1.3
General Disorders and Administration Site Conditions
Infusion site burning	0	3.7	0	0
Injection site pain	0	2.8	0	0
Peripheral edema	0	1.8	6.7	0
Nervous Systems Disorders
Dizziness	0	2.8	6.7	0
Headache	0	2.8	0	0
Vascular Disorders
Hypotension NOS	5.2	0	6.7	0
*NOS = Not otherwise specified

Adverse Events Observed in Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Patients

Adverse reactions, whether or not related to Venofer® (iron sucrose injection, USP) administration, reported by > 5% of treated patients from a total of 231 patients in HDD-CKD Studies A, B, and C were as follows: hypotension (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%).

In the first post-marketing safety study, 665 chronic hemodialysis patients were treated with Venofer® doses of 100 mg at each dialysis session for up to 10 consecutive dialysis sessions for their iron deficiency or on a weekly basis for 10 weeks for maintenance of iron stores. In this study, 72% of the patients received up to 10 doses, 27% received between 11-30 doses, and 1% received 40 to 50 doses of Venofer®. Serious adverse events and drug-related non-serious adverse events were collected. In the second post-marketing safety study, 386 hemodialysis patients were exposed to a single dose of Venofer® (100 mg IV by slow injection over 2 minutes or 200 mg IV by slow injection over 5 minutes). The mean age of patients enrolled into the two post-marketing safety studies was 59 years, with a range of 20-93 years. Males made up 60% of the population. The ethnicity of the patients enrolled in the two studies included Blacks (44%), Caucasians (41%), Hispanics (11%), Asians (3%), and others (1%). Adverse events reported by > 1% of 1,051 treated patients were: cardiac failure congestive, sepsis NOS and dysgeusia.

Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients

In Study D of 182 treated NDD-CKD patients, 91 were exposed to Venofer®. Adverse events, whether or not related to Venofer® , reported by ≥ 5% of the Venofer® exposed patients were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer® patient). Two patients experienced possible hypersensitivity/allergic reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer® group), three Venofer® patients had events that were considered drug-related (hypotension, dyspnea and nausea).

In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by ≥ 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), dysgeusia (7.7%), dizziness (6.6%), extremity pain (5.5%), and injection site burning (5.5%). No patient experienced a hypersensitivity/allergic reaction during the study. Of the patients who prematurely discontinued the treatment phase of the study due to adverse events (2.1% oral iron group and 12.5% Venofer® group), only one patient (Venofer® group) had events that were considered drug-related (anxiety, headache, and nausea). Ninety-one (91) patients in this study were exposed to Venofer® either during the treatment or extended follow-up phase.

Adverse Events Observed in Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) Patients

In Study E of 121 treated PDD-CKD patients, 75 patients were exposed to Venofer®. Adverse events, whether or not related to Venofer® reported by ≥ 5% of these patients are as follows: diarrhea, peritoneal infection, vomiting, hypertension, pharyngitis, peripheral edema and nausea.

In these 75 patients exposed to Venofer®, 9 patients experienced serious adverse events as follows: peritoneal infection (2 patients) and 1 patient each with cardiopulmonary arrest, myocardial infarction, upper respiratory infection NOS, anemia, gangrene, hypovolemia and tuberculosis. None of these events were considered drug-related. Two Venofer® patients experienced a moderate hypersensitivity/allergic reaction (rash or swelling/itching) during the study.

The only drug related adverse reaction to Venofer® administration reported by ≥ 2% of patients was diarrhea.

Three patients in the Venofer® study group discontinued study treatment due to adverse events (cardiopulmonary arrest, peritonitis and myocardial infarction, hypertension) which were considered to be not drug-related.

Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS.

In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg.

The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration.

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients were treated with Venofer® there were no occurrences of adverse events that precluded further use of Venofer®.

No information provided.

Last updated on RxList: 1/2/2008

Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS.

General

Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing. (See DOSAGE AND ADMINISTRATION and OVERDOSE).

Hypersensitivity Reactions

Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life- threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer. See ADVERSE REACTIONS.

Hypotension

Hypotension has been reported frequently in hemodialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®.

Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test.

Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy Category B

Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Venofer® is excreted in milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer® is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established.

Geriatric Use

Studies A through E did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post- marketing safety studies of Venofer®, 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Last updated on RxList: 1/2/2008

Dosages of Venofer® (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [5]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia.

Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms.

Preclinical Data

Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal.

The symptoms of acute toxicity were sedation, hypoactivity, pale eyes, and bleeding in the gastrointestinal tract and lungs.

REFERENCES

[5] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis 37: S182-S238, (suppl 1) 2001.

The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency.

Last updated on RxList: 1/2/2008

Pharmacodynamics: Following intravenous administration of Venofer®, iron sucrose is dissociated by the reticuloendothelial system into iron and sucrose. In 22 hemodialysis patients on erythropoietin (recombinant human erythropoietin) therapy treated with iron sucrose containing 100 mg of iron, three times weekly for three weeks, significant increases in serum iron and serum ferritin and significant decreases in total iron binding capacity occurred four weeks from the initiation of iron sucrose treatment.

Pharmacokinetics: In healthy adults treated with intravenous doses of Venofer®, its iron component exhibits first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, non-steady state apparent volume of distribution of 10.0 L and steady state apparent volume of distribution of 7.9 L. Since iron disappearance from serum depends on the need for iron in the iron stores and iron utilizing tissues of the body, serum clearance of iron is expected to be more rapid in iron deficient patients treated with Venofer® as compared to healthy individuals. The effects of age and gender on the pharmacokinetics of Venofer® have not been studied.

Venofer® is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of iron sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

Distribution: In healthy adults receiving intravenous doses of Venofer®, its iron component appears to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Venofer® containing 100 mg of iron labeled with ⁵²Fe/⁵⁹Fe in patients with iron deficiency shows that a significant amount of the administered iron distributes in the liver, spleen and bone marrow and that the bone marrow is an iron trapping compartment and not a reversible volume of distribution.

Metabolism and Elimination: Following intravenous administration of Venofer®, iron sucrose is dissociated into iron and sucrose by the reticuloendothelial system. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Venofer® containing 1,510 mg of sucrose and 100 mg of iron in 12 healthy adults (9 female, 3 male: age range 32-52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some iron also is eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration [1]. In this study and another study evaluating a single intravenous dose of iron sucrose containing 500-700 mg of iron in 26 anemic patients on erythropoietin therapy (23 female, 3 male; age range 16-60), approximately 5% of the iron was eliminated in urine in 24 h at each dose level [2].

Drug-drug Interactions: Drug-drug interactions involving Venofer® have not been studied. However, like other parenteral iron preparations, Venofer® may be expected to reduce the absorption of concomitantly administered oral iron preparations.

Clinical Trials

Venofer® is used to replenish body iron stores in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving erythropoietin and in NDD-CKD patients not receiving erythropoietin, and in hemodialysis dependent-chronic kidney disease (HDD-CKD) and peritoneal dialysis dependent- chronic kidney disease (PDD-CKD) patients receiving erythropoietin. Iron deficiency may be caused by blood loss during dialysis, increased erythropoiesis secondary to erythropoietin use, and insufficient absorption of iron from the gastrointestinal tract. Iron is essential to the synthesis of hemoglobin to maintain oxygen transport and to the function and formation of other physiologically important heme and non-heme compounds. Most dialysis patients require intravenous iron to maintain sufficient iron stores.

Six clinical trials were conducted to assess the safety and efficacy of Venofer®. Five studies were conducted in the United States (516 patients) and one was conducted in South Africa (131 patients).

Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 hemodialysis patients (77 patients with Venofer® treatment and 24 in the historical control group) with iron deficiency anemia. Eligibility for Venofer® treatment included patients undergoing chronic hemodialysis three times weekly, receiving erythropoietin, hemoglobin concentration greater than 8.0 and less than 11.0 g/dL for at least two consecutive weeks, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients in the treatment group was 65 years with the age range being 31 to 85 years of age. The erythropoietin dose was to be held constant throughout the study. The protocol did not require administration of a test dose; however, some patients received a test dose at the physician's discretion. Exclusion criteria included significant underlying disease, asthma, active inflammatory disease, or serious bacterial or viral infection. Venofer® 5 mL containing 100 mg of elemental iron was administered through the dialysis line at each dialysis session either as slow injection or a saline diluted slow infusion for a total of 10 dialysis sessions with a cumulative dose of 1,000 mg elemental iron. A maximum of 15 mLs (300 mg of elemental iron) of Venofer® was administered per week.

No additional iron preparations were allowed until after the Day 57 evaluation. The mean change in hemoglobin from baseline to Day 24 (end of treatment), Day 36, and Day 57 was assessed. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Venofer®, who were off intravenous iron for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31-36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients. Of the 77 patients in the treatment group, 44 (57%) were male and 33 (43%) were female. The mean baseline hemoglobin and hematocrit, were higher and erythropoietin dose was lower in the historical control population than the Venofer® treated population.

Patients in the Venofer® treated population showed a statistically significantly greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 1.

Table 1. Changes from Baseline in Hemoglobin and Hematocrit

Efficacy parameters	End of treatment 2 week follow-up 5 week follow-up
	Venofer® (n=69)	Historical Control (n=18)	Venofer® (n=73)	Historical Control (n=18)	Venofer® (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0±0.12**	0.0±0.21	1.3±0.14**	-0.6±0.24	1.2±0.17*	-0.1±0.23
Hematocrit (%)	3.1±0.37**	-0.3±0.65	3.6±0.44**	-1.2±0.76	3.3±0.54	0.2±0.86
**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.

Serum ferritin increased significantly (p=0.0001) at endpoint of study from baseline in the Venofer®- treated population (165.3±24.2 ng/mL) compared to the historical control population (-27.6±9.5 ng/mL). Transferrin saturation also increased significantly (p=0.0016) at endpoint of study from baseline in the Venofer®-treated population (8.8±1.6%) compared to this historical control population (-5.1±4.3%) [3].

Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Study B was a multicenter, open label study of Venofer® (iron sucrose injection, USP) in 23 iron deficient hemodialysis patients who had been discontinued from iron dextran due to intolerance. Eligibility criteria and Venofer® administration were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21-79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female. The ethnicity breakdown of patients enrolled in this study was as follows: Caucasian (35%); Black (35%); Hispanic (26%); Asian (4%). The mean change from baseline to the end of treatment (Day 24) in hemoglobin, hematocrit, and serum iron parameters was assessed.

All 23 enrolled patients were evaluated for efficacy. Statistically significant increases in mean hemoglobin (1.1±0.2 g/dL), hematocrit (3.6±0.6%), serum ferritin (266.3±30.3 ng/mL) and transferrin saturation (8.7±2.0%) were observed from baseline to end of treatment [4].

Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Study C was a multicenter, open-label, two period (treatment followed by observation period) study in iron deficient hemodialysis patients. Eligibility for this study included chronic hemodialysis patients with a hemoglobin less than or equal to 10 g/dL, a serum transferrin saturation less than or equal to 20%, and a serum ferritin less than or equal to 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16-70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. The ethnicity breakdown of patients enrolled in this study was as follows: Caucasian (23%); Black (23%); Asian (5%); Other (mixed ethnicity) (49%). Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies A and B. Venofer® was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of iron was administered.

Patients received Venofer® at each dialysis session, two to three times weekly. One hour after the start of each session, 5 mL iron sucrose (100 mg iron) in 100 mL 0.9% NaCl was administered into the hemodialysis line. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry. Patients were treated until they reached an individually calculated total iron dose based on baseline hemoglobin level and body weight. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

Changes from baseline to observation week 2 and observation week 4 (end of study) were analyzed.

The modified intention-to-treat population consisted of 131 patients. Significant (p < 0.0001) increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained significantly increased (p < 0.0001) at week 4 of the observation period.

Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral iron versus intravenous iron sucrose (Venofer®) in NDD-CKD patients with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL and an average baseline hemoglobin of ≤ 11.0 g/dL were randomized to receive oral iron (325 mg ferrous sulfate three times daily for 56 days); or Venofer® (either 200 mg over 2-5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5-4 hours). Of the 188 randomized patients, 182 were treated and followed for up to 56 days. Efficacy assessments were measured on days 14, 28, 42 and 56. The mean age of the 91 treated patients in the Venofer® group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral iron group. Ethnicity breakdown of the patients in the Venofer® group was as follows: Caucasian (60.4%), Black (34.1%), Hispanic (3.3%), Other (2.2%). Ethnicity breakdown for the oral iron group was: Caucasian (50.5%), Black (44.0%), Hispanic (4.4%), Other (1.1%). Patient demographic characteristics were not significantly different between the groups. A statistically significantly greater proportion of Venofer® subjects (35/79; 44.3%) compared to oral iron subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p= 0.03). In patients ≥ 65 years of age, the proportion of subjects achieving ≥ 1.0 g/dL increase in hemoglobin from baseline was 53% (20/38) in the Venofer® group compared to 23% (10/43) in the oral iron group. In patients < 65 years of age, the proportion of subjects achieving ≥ 1.0 g/dL increase in hemoglobin from baseline was 37% (15/41) in the Venofer® group compared to 33% (13/39) in the oral iron group. A statistically significantly greater proportion

of Venofer® treated patients (31/79; 39.2%) compared to oral iron treated patients (1/82; 1.2%) had an increase in hemoglobin ≥ 1 g/dL and ferritin ≥ 160 ng/mL at anytime during the study (p < 0.0001).

Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)

Study E was a randomized [2:1 treatment: control], open-label, multicenter study comparing PDD- CKD patients receiving an erythropoietin and IV iron to PDD-CKD patients receiving an erythropoietin alone without iron supplementation. 126 patients with PDD-CKD, stable erythropoietin for 8 weeks, TSAT ≤ 25%, Ferritin ≤ 500 ng/mL and an average baseline hemoglobin of ≤ 11.5 g/dL were randomized to receive either no iron or Venofer® (iron sucrose injection, USP) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). 121 of the 126 randomized patients were treated and followed for up to 71 days with a total of 88 patients who completed the study. Efficacy assessments were measured on days 15, 29, 43, 57 and 71. Patient demographic characteristics were not significantly different between the groups. The mean age of the 75 treated patients in the Venofer® / erythropoietin group was 51.9 years, (range 21 to 81 years) vs. 52.8 years, (range 23 to 77 years) for 46 patients in the erythropoietin alone group. Ethnicity breakdown of the patients in the Venofer® / erythropoietin Group was as follows: Caucasian (36%); Hispanic (32%); Black (21.3%); Other (10.7%). Ethnicity breakdown for the erythropoietin alone group was: Hispanic (43.5%); Caucasian (30.4%); Black (15.2%); Other (10.9%). Patients in the Venofer® / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A statistically significantly greater proportion of subjects treated with Venofer® / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%) (p < 0.05).

REFERENCES

[1] Danielson, et al.; Drug Research 46:615-621, 1996.

[2] Anatkov and Gekova; Problems of Hem. Bld. Transfsns., Med Physioculture, 13:295-298, 1970.

[3] Charytan, et al.; Am J Kidney Dis 37:300-307, 2001.

[4] Van Wyck, et al.; Am J Kidney Dis 36:88-97, 2000.

[5] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis 37: S182-S238, (suppl 1) 2001.

Last updated on RxList: 1/2/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 1/2/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

IRON SUCROSE - INJECTION

(iron SOO-krose)

COMMON BRAND NAME(S): Venofer

USES: This medicine is used to treat "iron-poor" blood (anemia) in people with long-term kidney disease. You may need extra iron because of blood loss during kidney dialysis. Your body may also need more iron if you use the drug erythropoietin to help make new red blood cells.

Iron is an important part of your red blood cells and is needed to transport oxygen in the body. Many patients with kidney disease cannot get enough iron from food and require injections.

HOW TO USE: Inject this medication into a vein (IV) slowly over 2 to 5 minutes. Iron sucrose can also be mixed in a saline solution and given through an IV over a longer time. Inject this medication as your doctor directs.

Follow all instructions for proper mixing and dilution with the correct IV fluids. Do not mix iron sucrose with other IV medications. If you have questions regarding the use of this medication, consult your pharmacist.

Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

Only newly opened containers (vials) should be used. Do not keep any medication left over in the vial after your dose. Learn how to store and discard needles and medical supplies safely. Consult your pharmacist.

Your dosage and length of treatment are based on your medical condition and response to therapy. Your doctor will take blood tests to monitor your response.

SIDE EFFECTS: Muscle cramps, nausea, vomiting, strange taste in the mouth, diarrhea, constipation, headache, cough, back pain, joint pain, dizziness, or swelling of the arms/legs may occur. Pain, swelling, or redness at the injection site may occur. If these effects continue or worsen, tell your doctor.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Severe dizziness or fainting (hypotension) may occur while you are receiving IV iron. This may be helped by giving the medication more slowly or at a lower dose. Follow your doctor's directions carefully.

Tell your doctor immediately if you have any of these unlikely but serious side effects: abdominal pain, chest pain, irregular heartbeat (arrhythmias), pressure in the chest, severe headache and blurred vision (hypertension), problems with your dialysis access site (graft).

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, severe dizziness, swelling, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using iron sucrose, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Tell your doctor of all prescription and nonprescription medication you may use, especially of: vitamin products, other iron-containing products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If you or someone you know may have used more than the recommended dose of this medicine, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Periodic blood tests will be done to check your response to this medication. Make sure to keep all your medical and laboratory appointments.

It is important to maintain a well balanced diet to ensure adequate intake of iron, vitamins and minerals. Good sources of iron include meats (especially liver), eggs, raisins, figs, broccoli, brussels sprouts, beans, lentils, and iron-fortified or enriched cereals. Follow diet recommendations for your condition.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59 and 86 degrees F (15 to 30 degrees C). Do not refrigerate.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.